Novel method of administering anti-nausea and anti-emetic pharmaceutical agents and novel dosage forms containing same

ABSTRACT

Invention relates to nasal administration of known anti-nausea and anti-emetic therapeutic agents and dosage forms useful for such administration.

RELATED APPLICATIONS

This application is a continuation in part of application Ser. No.671,694 filed Nov. 11, 1984 which is, in turn a continuation in part ofapplication Ser. No. 663,891 filed Oct. 23, 1984 and now abandoned.

BACKGROUND OF INVENTION

1. Field of the Invention

The present invention relates to a novel method of administering antinausea and anti emetic agents and to novel dosage forms containing suchagents adapted for nasal administration.

The invention provides a novel method of administering therapeuticagents that inhibit nausea and emesis in mammals induced by stimulationof either the chemoreceptor trigger zone or the emesis (or vomiting)center in the central nervous system. Such stimulation can be caused byafferent stimulation (e.g., tactile pharyngeal impulses, labrynthinedisturbances, motion, increased intracranial pressure, pain, distentionof viscera or psuchologic factors) or blood borne emetic substances(e.g., as seen during pregnance, cancer chemotherapy, uremia, radiationtherapy, electrolyte and endocrine disturbances, or the presence ofchemical emetic substances).

The invention further provides dosage forms of those agents which areadapted for nasal administration and which include solutions,suspensions, sustained release formulations, gels and ointments. Thetherapeutic agents include selected antihistamines, anticholinergics,piperazines, phenothiazines, substituted butyprophenes andmetoclopramide.

2. Background Art

A number of anti nausea and anti emetic agents are already known. Suchagents are widely used therapeutically, chiefly in the treatment ofemesis and nausea, and certain of the agents in the treatment ofvertigo, motion-sickness, hypersensitivity phenomena (anaphylaxis andallergy), rhinitis, sinusitis and gastroesophageal reflux disease.Unfortunately, many of these agents when used: [1] cause undesirableside effects, [2] are inefficiently and variably absorbed from currentdosage forms, [3] are difficult or inconvenient to administer in thecurrent dosage forms after the onset of emesis or nausea, and [4] havedelayed onset of pharmacological activity when administered by currentdosage forms. It has now been unexpectedly discovered that thesepharmacologically active agents can be administered by nasal delivery toprovide: enhanced bioavailability, minimized variations in blood levelsmore rapid onset of activity and reduced dosages when compared to mostcurrent methods of administration (e.g., oral, subcutaneous,intra-muscular or by way of suppository).

Nasal delivery of therapeutic agents has been well known for a number ofyears. See, for example, U.S. Pat. Nos. 4,428,883; 4,284,648 and4,394,390; and PCT application International Publication No. WO83/00286.See also, Hussain et al, J. Pharm. Sci: 68, No. 8, 1196 (1979); 69 1240(1980) and 69 1411 (1980).

The PCT document describes nasal compositions for the administration ofscopalamine, a parasympathetic blocking agent but fails to teach orrecognize that a therapeutic response can be elicited at a dosage levelwhich is only a fraction of that normally employed.

It should also be mentioned that while nasal administration of certaintherapeutic agents to mammals, especially humans is known it is not anecessary conclusion from such knowledge that all therapeutic agents canbe usefully administered by this route. In fact it has been shown thatmany drugs cannot be usefully administered by the nasal route. Itcertainly is not a suggestion that the selected anti-nausea andanti-emetic compounds of this invention which are not parasympatheticblocking agents can be usefully administered nasally to achieve enhancedbioavailability and sustained therapeutic blood levels.

SUMMARY OF INVENTION

It has been discovered that known anti nausea and anti emetic agents,the formulas of which are shown below can be usefully administered tomammals in novel compositions at extremely low dosage levels to elicit asystemic therapeutic response and to provide enhanced bioavailability,minimized variations in blood levels, more rapid onset of activity, easeof administration, and reduced side effects compared to most currentmethods of administration. Specifically, the blood levels of atherapeutic agent achieved by nasal administration can be substantiallythe same as the levels achievable with oral dosage units containing asmuch as ten times the amount of the same therapeutic agent. The nasaladministration process of this invention is significently moreconvenient than parenteral administration. Simple aerosol containers, oreye droppers which can be easily carried in a pocket or purse can beused for delivery. This should be compared with hypodermic needles whichare difficult to use and repugnant to most people. In many jurisdictionsit is illegal to transport them.

DETAILED DESCRIPTION OF THE INVENTION

The selected therapeutic agents for use in the compositions and methodsof the present invention are brompheniramine, promethazine,cyproheptadine, dimenhydrinate, meclizine cyclizine, chlorcyclizine,buclizine, trimethobenzamide, benzquinamide metoclopramide,diphenhydramine, doxylamine, methapyrilene and tripelennamine.

Any pharmaceutically acceptable form of the therapeutic agents can beemployed, i.e., the free base or a pharmaceutically acceptable saltthereof (e.g., cyclizine hydrochloride, cyclizine acetate,diphenhydramine hydrochloride, meclizine hydrochloride, promethazinehydrochloride, etc.) Generally the selected therapeutic agent isemployed in the instant compositions and method in the pharmaceuticallyacceptable form which has previously been found most advantageous fororal or parenteral use. The structural formulae for certain of the freebases emcompassed by the present invention are set forth below: ##STR1##

These therapeutic agents and their methods of preparation are wellknown.

Cyclizine, chlorcyclizine, meclizine, and buclizine are allantihistimines and piperazine derivatives. They are referred to hereinas the meclizine family and are preferred for use in this inventionbecause of their ready availability and their high activity even atextremely low concentration. Metoclopramide is another preferredcompound for use in this invention because when low dosages areadministered nasally high blood levels are rapidly achieved andmaintained for a long period of time.

In accordance with the present invention, the selected drugs named supracan be administered nasally to humans or other mammals with resultsconsiderably superior to those obtained with oral administration interms of enhanced drug bioavailability and minimization of blood levelvariations, thus enabling use of these drugs at lower dosage levels thanwas previously possible except in the case of intravenousadministration. It would appear that these selected drugs are rapidlyabsorbed from the nasal mucosa into systemic blood without first-passmetabolism.

Any of the selected drugs identified above can be convenientlyadministered nasally to warm-blooded animals to elicit a systemic,therapeutically anti-nausea or anti-emetic response by formulating itinto a nasal dosage form comprising the desired drug, in a systemic,therapeutically effective anti-nausea or anti-emetic amount, togetherwith a nontoxic pharmaceutically acceptable nasal carrier thereof. Asindicated earlier, the drug can be employed in the form of the free baseor in the form of a pharmaceutically acceptable salt. Suitable nontoxicpharmaceutically acceptable nasal carriers will be apparent to thoseskilled in the art of nasal pharmaceutical formulations. For those notskilled in the art, reference is made to the text entitled "REMINGTON'SPHARMACEUTICAL SCIENCES", 14th edition, 1970. Obviously, the choice ofsuitable carriers will depend on the exact nature of the particularnasal dosage form required, e.g., whether the drug is to be formulatedinto a nasal solution (for use as drops or as a spray), a nasalsuspension, a nasal ointment, a nasal gel or another nasal form.Preferred nasal dosage forms are solutions, suspensions and gels, whichnormally contain a major amount of water (preferably purified water) inaddition to the active ingredient. Minor amounts of other ingredientssuch as pH adjusters (e.g., a base such as NaOH), emulsifiers ordispersing agents, buffering agents, preservatives, wetting agents andjelling agents (e.g., methylcellulose) may also be present.

Most preferably, the nasal composition is isotonic, i.e., it has thesame osmotic pressure as blood serum. If desired, sustained releasenasal compositions, e.g., sustained release gels, or when a more highlyinsoluble form is desired, a long chain carboxylic acid salt of thedesired drugs can be conveniently employed. The carboxylic acid portionof the salt preferably contains 10 to 20 carbon atoms. Such salts (e.g.,stearates, palmitates etc.) can be readily synthesized, for example, bydissolving the hydrochloride salt of the drugs in water, then adding thealkali metal salt of the desired long chain carboxylic acid (e.g.,sodium stearate). The corresponding long chain carboxylic acid saltwhich precipitates out of solution is removed by filtration.Alternatively, equimolar amounts of the drug free base and the longchain carboxylic acid are combined in methanol. That mixture is thenadded to a small volume of water, causing the desired salt (e.g., drugstearate) to precipitate out.

Those skilled in the art will be aware that a systemic, therapeuticallyeffective anti-nausea or anti-emetic amount of a particular agent willvary with the particular agent, the age, size, weight and generalphysical condition of the patient. Typically the dosage level will bemore similar to the expected dosage level for intravenous administrationthan to the dosage levels currently employed for other methods ofadministration, for example oral, rectal or subcutaneous.

As a practical matter the selected therapeutic compositions willnormally be prepared in dosage unit forms to contain systemic,therapeutically effective amounts of the selected anti-nausea oranti-emetic agent. In specific instances fractions of the dosage unitsor multiple dosage units will be employed. Typically dosage units may beprepared to deliver 5 mg to 75 mg of therapeutic agent per 0.2 cc ofsolution or gel, these being the preferred types of compositions.

The following examples are given by way of illustration only and are notto be considered limitations of this invention many apparent variationsof which are possible without departing from the spirit or scopethereof.

EXAMPLE 1

The following compositions are prepared as illustrative aqueoussolutions of the named drugs suitable for use as nasal drops or nasalspray. In each case, the pH of the final composition is adjusted to 7.4with NaOH. The solutions are adjusted to isotonicity with NaCL.

    ______________________________________                                        COMPOSITION A                                                                 diphenhydramine hydrochloride                                                                          500    mg                                            Tween 80                 2      mg                                            methylcellulose          20     mg                                            water, purified          10     ml                                            Final concentration 50 mg/0.2 cc                                              COMPOSITION B                                                                 dimenhydrinate           2500   mg                                            Tween 80                 4      mg                                            methylcellulose          20     mg                                            water, purified          10     ml                                            Final concentration 50 mg/0.2 cc                                              COMPOSITION C                                                                 metoclopramide hydrochloride                                                                           500    mg                                            Tween 80                 2      mg                                            methylcellulose          20     mg                                            water, purified          10     ml                                            Final concentration 10 mg/0.2 cc                                              ______________________________________                                    

EXAMPLE 2

Two Sprague-Dawley male rats each weighing 250 to 300 grams,anesthetized using sodium pentobarbitol (50 mg/Kg of body weight), wereadministered nasally by micropipet a dosage level of 15 mg/Kg of bodyweight of the following composition:

216 mg metoclopramide.HCL (MCP.HCL)

292 mg 6.5% Tween 80 in Saline

895.2 mg polycthylene glycol (PEG 400)

522.2% mg polyethylene glycol (PEG 3350)

74.6 mg Stearyl-Alcohol

The femoral artery was cannulated with heparinized polyethylene tubing(Clay Adams, PE-50) and blood samples were removed at the timesindicated in Table 1.

The samples are analyzed by high pressure liquid chromatography (HPLC)as follows:

    ______________________________________                                        Column       Silica Column (4.6 × 250 mm)                               Detection    308 nm                                                           Mobile Phase CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH = 90:10:0.5                  Flow Rate    1.7 ml/min                                                       ______________________________________                                    

Plasma (0.3 ml) was placed in a test tube and 0.1 ml of 1N NaOH wasadded. Four ml of methylene chloride was then added and the mixtureskaken for 10 minutes on a reciprocal shaker, centrifuged for 3 minutesin an IEC clinical centrifuge and the upper layer removed by aspiration.A 3.0 ml aliquot of the methylene chloride layer was transferred to asecond table and evaporated to dryness with a stream of nitrogen gas.The resulting residue was then dissolved in 0.1 to 0.5 ml of mobilephase and submitted to HPLC analysis.

The results are shown in Table 1.

    ______________________________________                                        Nasal Absorption                                                              (Nasal Formulation)                                                           Time        Concentration*                                                    (min)       (μg/ml plasma)                                                 ______________________________________                                        0           0                                                                 5           0.96 ± 0.12                                                    10          1.41 ± 0.10                                                    15          1.61 ± 0.23                                                    30          1.55 ± 0.18                                                    45          1.30 ± 0.18                                                    60          1.26 ± 0.3                                                     75          1.11 ± 0.34                                                    90          1.04 ± 0.35                                                    120         1.10 ± 0.38                                                    180         1.09 ± 0.36                                                    240         0.94                                                              ______________________________________                                         *Mean ± S.D. (n = 3)                                                  

It will be noted that the concentration is measurable after only 5minutes, reaches maximum concentration in 15 minutes and sustains a highlevel for at least 4 hours.

EXAMPLE 3

The procedure of Example 2 was repeated with three rats except that theMCP.HCL was administered at the same dosage level in isotonic sodiumchloride. The results are shown in Table 2.

    ______________________________________                                        Nasal Absorption                                                              (Solution - Saline)                                                           Time        Concentration*                                                    (min)       (μg/ml plasma)                                                 ______________________________________                                        0           0                                                                 5           0.42 ± 0.05                                                    10          0.68 ± 0.10                                                    15          0.85 ± 0.12                                                    30          1.37 ± 0.21                                                    45          1.51 ± 0.18                                                    60          1.61 ± 0.05                                                    75          1.62 ± 0.17                                                    90          1.63 ± 0.18                                                    120         1.55 ± 0.26                                                    150         1.55 ± 0.21                                                    240         1.29 ± 0.28                                                    ______________________________________                                         *Mean ± S.D. (n = 3)                                                  

It will be observed that the time to achieve maximum levels wasextended, but that the high levels were maintained for a longer periodof time.

EXAMPLE 4

A female beagle dog weighing about 10 Kg was anesthetized with sodiumpentobarbitol (30 mg/kg of body weight).

The following composition was administered to the nasal cavity using asyringe at a dose of 10 mg of MCP:

50 mg of MCP

200 mg of 5% Tween 80

430 mg of PEG 400

280 mg of PEG 3350

40 mg of stearyl alcohol

A catheter was inserted into the cubital vein and the blood samples werecollected at the indicated times shown in the following Table 3.

The samples were analyzed by HPLC as follows:

HPLC Analysis

    ______________________________________                                        Column       Silica column (Altex 4.6 × 250 mm)                         Detection    308 nm                                                           Mobile Phase CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH = 90:10:0.5                  Flow Rate    1.7 ml/min                                                       ______________________________________                                    

Plasma (2.0 ml) was placed in a test tube and 0.5 ml of 1N NaOH wasadded. Seven ml of methylene chloride was then added and the mixture wasshaken for 10 min on a reciprocal shaker, centrifuged at 2000 rpm for 3min, and the upper layer was removed by aspiration.

A 6.0 of aliquot of the methylene chloride was transferred to a secondtube and evaporated to dryness with a stream of nitrogen gas. Theresulting residue was then dissolved in 0.4 ml of mobile phase andsubmitted to HPLC analysis.

                  TABLE 3                                                         ______________________________________                                        Nasal-Absorption                                                              Time        Concentration                                                     (min)       (ng/ml plasma)                                                    ______________________________________                                        0           0                                                                 5           48.1                                                              10          62.5                                                              15          78.6                                                              30          90.5                                                              60          112.7                                                             90          102.8                                                             120         84.2                                                              180         82.0                                                              240         72.2                                                              300         56.9                                                              360         53.1                                                              ______________________________________                                    

EXAMPLE 5

The procedure of Example 4 was repeated except that the MCP.HCL wasadministered at the same dosage level in isotonic sodium chloride. Theresults are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Nasal Absorption                                                              (Solution-Saline)                                                                         Concentration                                                            Time (ng/ml plasma)                                                    ______________________________________                                                0   0                                                                         5   74.4                                                                     10   98.9                                                                     15   150.8                                                                    30   162.8                                                                    60   103.6                                                                    90   90.5                                                                     120  68.2                                                                     180  60.8                                                                     240  49.1                                                                     300  38.4                                                                     360  34.2                                                              ______________________________________                                    

EXAMPLE 6

Seven Wister rats weighing from 250 to 275 gr (Charles RiverLaboratories, Inc., Wilmington, MA) were anesthetized with 50 mg/kg i.p.sodium pentobarbitol. The neck was surgically opened, and a polyethylenetube (PE 260, Intramedic Clay Adams) was inserted into the trachea andtied in place. Another PE tube was inserted into the esophagus to theposterior of the nasal cavity and also secured. The juglar veins wereexposed and the nasopalatine was closed with glue (Super Glue, WoodhillPermetex, Cleveland, OH). Meclizine dihydrochloride at a concentrationof 6.4 mg/ml in normal saline containing 2% Tween 80 was injected atdosage levels of 0.64 mg/rat and 1.28 rat by syringe through the tubeinto the nasal cavity. Blood (0.2-0.3 ml) was sampled at various timesfrom the juglar veins, alternating left and right, and stored on ice inpreheparinized microfuge tubes.

Extraction of meclizine from whole blood was performed by the method ofHom and Ebert. J. Pharm. Sci 66: 710 (1977). Briefly, whole heparinizedblood was centrifuged on a Beckman Microfuge B, and 0.1 ml of plasmacollected. One normal HCL (0.4 ml) was added to this in anothermicrofuge tube, and the mixture was vortexed for 30 seconds. One ml ofchloroform was then added, the samples vortexed for an additionalminute, and then centrifuged again. The entire chloroform phase wasremoved, transferred to a test tube, and evaporated to dryness with aBuchler Evapomix. The extract was resuspended in 0.2 ml of HPLC solventand duplicate samples were injected into the HPLC for analysis.

For HPLC a Waters Corp., Milford, MA, system was utilized. Thisconsisted of models 720 B WISP autosampler, both 480 Lamda-Max variableand 440 dual-channel UV detectors, 660 solvent programmer, 730 datamodule, M6000A and M-45 pumps, and a 3.9×150 mm Novapak C₁₈ column (5 mparticle size) preceded by a 3.9×23 mm Corasil (particle size, 30-38 m)C₁₈ filled guard column. The conditions for HPLC were isocratic 23:770.1M sodium acetate (PH 4.3) methanol, flow rate 1.0 ml/min anddetection at 232 nm.

The results of the analysis are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Nasal-Absorption                                                                           Concentration                                                                 (ng/ml plasma)                                                   Time           0.64    1.28                                                   (min)          Dosage  Dosage                                                 ______________________________________                                        2               70     210                                                    4              250     720                                                    6              300     960                                                    8              630     1100                                                   15             620     970                                                    30             440     720                                                    45             250     530                                                    60             230     --                                                     75             210     --                                                     90             190     340                                                    120            110     --                                                     150            100     180                                                    180             80     --                                                     210             70     120                                                    240             70     --                                                     ______________________________________                                    

EXAMPLE 7 TOXICITY STUDIES IN RABBITS

A group of twenty rabbits were divided into 14 test and 6 controlanimals. The test animals were administered 20 mg of the following gelcomposition:

Formulation to make 100 ml at 100 mg/cc

    ______________________________________                                                           Formulation to                                                                make 100 ml at                                                                100 mg/cc                                                  ______________________________________                                        BENZYL ALCOHOL N.F.        1.500   ml                                         SODIUM CHLORIDE            0.800   grams                                      METHOCEL 4000 U.S.P.       2.000   grams                                      ACETIC ACID N.F.           0.320   grams                                      SODIUM ACETATE U.S.P.      0.077   grams                                      SORBITOL SOLUTION U.S.P.   5.000   ml                                         METOCLOPRAMIDE HCL         10.000  grams                                      WATER PURIFIED U.S.P.                                                                             q.s.   100.000 ml                                         ______________________________________                                    

by nasal instillation at 8, 12 and 16 hours for a total of fourteendays. The control animals were similarly treated with isotonic salinesolution.

Animals administered the metoclopramide gel formulation gained weightover the 14 days of the test period. No significant clinicalobersvations were noted among the test animals, and treated nostrilsappeared normal at all times, as compared to the untreated nostrils.Similar results were found among animals receiving the saline controlsolution.

Histopathological examination of the nasal cavities of animalssacrificed at 24 hours, 7 days and 14 days after initiation of the test,revealed no lesions which could be attributed to treatment with the testformulation. Nasal mucosal inflammation and exudate accumulation were nogreater than normal background findings, and rhinitis was not higherthan anticipated in conventional rabbits. Hemorrhage or blood present inthe nasal cavity was considered postmortum hemorrhage. Other lesionswere considered normal background lesions, not directly attributed tothe test formulation.

Two animals died on test. The death of one rabbit from the control groupwas attributed to mucoid enteropathy, a common malady in laboratoryrabbits. The death of the rabbit from the test group was tentativelyattributed to intussusception, not an uncommon finding in rabbits. Therewas no evidence for an association between the administration of thetest formulation and the death of this animal.

Examination of the nasal cavities from rabbits administered theformulation containing metoclopramide revealed no lesions which could beattributed to treatment with the test composition. The treated nasalcavities were not significantly different from untreated reference nasalcavities, or from those treated with the saline control.

EXAMPLE 8

A 4-way crossover study was conducted in eight volunteer human subjectsto compare the effects of the nasal administration of 5 and 10 mg ofmetoclopramide hydrochloride in a gel formation, 10 mg of the same agentin an oral formulation and 5 mg of the product intramuscularly. Thenasal formulation had the following composition:

Formulation to make 100 ml at 100 mg/cc

    ______________________________________                                                           Formulation to                                                                make 100 ml at                                                                100 mg/cc                                                  ______________________________________                                        BENZYL ALCOHOL N.F.        1.500   ml                                         SODIUM CHLORIDE U.S.P.     0.800   grams                                      METHOCEL 4000 U.S.P.       2.000   grams                                      ACETIC ACID, N.F.          0.320   grams                                      SODIUM ACETATE U.S.P.      0.077   grams                                      SORBITOL SOLUTION U.S.P.   5.000   ml                                         METOCLOPRAMIDE HCL         5.000   grams                                      WATER PURIFIED U.S.P.                                                                             q.s.   100.000 ml                                         ______________________________________                                    

The oral and intramuscular compositions were commercial formulationsavailable from A. H. Robbins Pharmaceutical Company, Richmond, VA. underthe name Reglan.

Substantially equivalent maximum blood levels were achieved with the 10mg nasal, 10 mg P.O. and 5 mg I.M. The pharmacokinetic profiles forthese doses were statistically identical. No evidence of local toxicitywas observed during or after the study.

The results are shown in the following table:

    ______________________________________                                        TIME TO PEAK AND ELIMINATION RATE CONSTANTS                                   (K.sub.el) FOLLOWING THE ADMINISTRATION OF                                    METOCLOPRAMIDE HCL ORALLY (PO) 10 MG,                                         INTRAMUSCULARLY (IM) 5 MG, AND INTRANASALLY                                   (IN) 5 AND 10 MG IN HUMAN SUBJECTS (n = 8)                                           PO       IM       5 IN       10 IN                                     ______________________________________                                        Peak Concn.                                                                            36.0(7.3)  34.0(3.3)                                                                              15.2(5.4)                                                                              35.1(7.6)                               (ng/ml)                                                                       Time to Peak                                                                           97.5(21.2) 91.9(39.6)                                                                             80.6(36.7)                                                                             131.3(39.1)                             (min.)                                                                        K.sub.el (K 10.sup.3)                                                                  1.89(1.13) 2.67(1.00)                                                                             2.59(1.41)                                                                             2.77(1.26)                              ______________________________________                                    

The study was extended to dosage levels of 20 mg and 40 mg by theintranasal route using the same compositions. Useful blood levels wereachieved. There was no evidence of either local or systemic toxicity inthe human subjects either before or after completion of the study.

EXAMPLE 9

H. F. was a 55 year-old female with Stage IV ovarian cancer. The patientfailed conventional chemotherapy and developed a complete bowelobstruction secondary to tumor growth in February, 1985.

Because of repeated nausea and vomiting due to bowel obstruction andother factors, intranasal metoclopramide at 40 mg per dose every fourhours was employed for control of symptoms. The intranasalmetoclopramide contained her nausea between occasional bouts of vomitingwhich were inevitable secondary to the mechanical bowl obstruction. Thepatient had previously not responded to anti-emetic suppositories givenfor nausea.

The formulation of the gel compositions was the same as in Example 7.

The study was extended to five more cancer patients who were previouslyrefractory to other antinausea treatments with the same formulation andsame dosage schedule. All patients benefited from the treatment and fourpreferred this route of administration over intraveneous injections.

What is claimed is:
 1. A method of eliciting a systemic, therapeutic, anti-nausea or anti-emetic response in a mammal which comprises nasal administration to said mammal of a systemically, therapeutically effective anti-nausea or anti-emetic amount of metoclopramide, or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable nasal carrier therefor.
 2. A method as in claim 1 wherein the pharmaceutically acceptable salt is a salt of a carboxylic acid containing from about 10 to 20 carbon atoms.
 3. A method as in claim 1 wherein the therapeutic agent is metoclopramide.
 4. A pharmaceutically acceptable composition for nasal administration in the form of a nasal solution, suspension, ointment or gel to obtain a systemic, therapeutic anti-nausea or anti-emetic response in a mammal comprising a systemically effective therapeutically effective amount of an anti-nausea or anti-emetic therapeutic agent selected from the group consisting of metoclopramide or a pharmaceutically acceptable acid addition sald thereof together with a pharmaceutically acceptable nasal carrier therefor.
 5. A composition as in claim 4 wherein the pharmaceutically acceptable salt is a salt of a carboxylic acid containing from about 10 to 30 carbon atoms.
 6. A composition as in claim 4 in dosage unit form.
 7. A composition as in claim 5 in dosage unit form. 